During the last decade, the number of fractures related to osteoporosis, i.e. reduced bone mass and changes in microstructure leading to an increased risk of bone fractures, has almost doubled. Due to the continuously increasing average life time it is estimated that by 2020 people over 60 years of age will represent 25% of Europe's population and that 40% of all women over 50 years of age will suffer from an osteoporotic fracture.
With the aim to reduce or eliminate the need for bone grafting, research has been made to find a suitable artificial bone mineral substitute. Presently, at least the following bone mineral substitutes are used for the healing of bone defects and bone fractures, namely calcium sulphates, as for instance Plaster of Paris, calcium phosphates, as for instance hydroxylapatite, and polymers, as for instance polymethylmetacrylate (PMMA).
Calcium sulphate (Plaster of Paris), CaSO4.½H2O, was one of the first materials investigated as a substitute for bone grafts. Studies have been undertaken since 1892 to demonstrate its acceptance by the tissues and rapid rate of resorbtion It has been concluded that Plaster of Paris implanted in areas of subperiosteal bone produces no further untoward reaction in the tissue than normally is present in a fracture. Regeneration of bone in the area of subperiosteal resection occurs earlier than when an autogenous graft is used. Plaster of Paris does not stimulate osteogenesis in the absence of bone periosteum. The new bone growing into Plaster of Paris is normal bone. No side effects attributable to the implantation of Plaster of Paris have been noted in adjacent tissues or in distant organs. However, Plaster of Paris has the drawback of very long setting times, which constitutes problems at surgery.
Another group of materials for substituting bone tissue in fracture sites and other bone defects is calcium phosphate cements. Due to their biocompatibility and their osteoconductivity they can be used for bone replacement and augmentation.
Hydroxylapatite, a crystalline substance which is the primary component of bone, is mainly used as a bone substitute, but is not strong enough for use under weight bearing conditions. Experiments have shown that hydroxy-lapatite cement forms a stable implant in respect of shape and volume over 12 months and has the same excellent tissue compatibility as exhibited by commercial ceramic hydroxylapatite preparations. Microscopic examination clearly demonstrated that hydroxylapatite cement was progressively ingrown by new bone over time.
Although the ideal is to achieve hydroxylapatite, there are also apatite-like calcium phosphates which can be obtained as potential bone substitutes. In Table 1 calcium phosphates are presented which are formed by a spontaneous precipitation at room or body temperature, as well as the pH range, within which these components are stable.
TABLE 1Calcium phosphates obtained byprecipitation at room or body temperatureCa/PFormulaNamepH0.5Ca(H2PO4)•H2OMCPM0.0-2.01CaHPO4•2H2ODCPD2.0-6.01.33Ca8(HPO4)2(PO4)4•5H2OOCP5.5-7.01.5Ca9(HPO4) (PO4)5OHCDHA6.5-9.51.67Ca5(PO4)3OHPHA9.5-12 
Other calcium phosphates can be obtained by means of sintering at high temperatures, above 1000° C. (Table 2). These calcium phosphates can not be obtained by precipitation in room or body temperature. However, they can be mixed with an aqueous solution alone or in combinations with other calcium phosphates to form a cement-like paste which will set with time.
TABLE 2Components forming calcium phosphate cementsCa/PCompoundFormulaName1.5α-tricalciumα-Ca3(PO4)2α-TCPphosphate1.5β-tricalciumβ-Ca3(PO4)2β-TCPphosphate1.67SinteredCa10(PO4)6(OH)2SHAhydroxylapatite2.0TetracalciumCa4(PO4)2OTTCPphosphate
Bone mineral substitute materials can be used for preparing a paste which can be injected directly into a fracture site. The paste is injected into the void in the bone and, upon hardening, an implant is obtained which conforms to the contours of the gap and supports the cancellous bone. Both calcium sulphate and hydroxylapatite materials have been extensively investigated as a possible alternative to autogenous bone grafts to help restore osseous defects of bone and fixation of bone fracture.
In this connection it is important that a complete stability is obtained as quickly as possible during or after surgery in order to prevent motions at site of healing. This especially applies to fractures, but also when filling of a bone cavity or replacing bone lost during tumor removal the healing is inhibited by movements and the ingrowth of new bone is prevented. Thus, the injected material must cure fast and adhere firmly to the bone tissue.
It is also of importance that the hardened material is so similar in structure to the bone so that it can be gradually resorbed by the body and replaced by new bone growth. This process can be facilitated if the hardened cement is provided with pores, which can transport nutrients and provide growth sites for new bone formation.
M. Bohner et al. disclosed at the Sixth World Bio-materials Congress Transactions (May 15-20, 2000) a method to obtain an open macroporous calcium phosphate block by using an emulsion of a hydrophobic lipid (oil) in an aqueous calcium phosphate cement paste or an emulsion of an aqueous calcium phosphate cement paste in oil. After setting, the cement block was sintered at 1250° C. for 4 hours. Likewise, CN 1193614 shows a porous calcium phosphate bone cement for repairing human hard tissue. The cement contains pore-forming agent which may be a non-toxic surfactant, or a non-toxic slightly soluble salt, acidic salt and alkaline salt.
Studies have also been made on mixtures of the above mentioned bone mineral substitute materials. In U.S. Pat. No. 4,619,655 is disclosed a bone mineral substitute material comprising a mixture of Plaster of Paris, i.e. calcium sulphate hemihydrate, and calcium phosphate ceramic particles, preferably composed of hydroxylapatite, or tricalcium phosphate or mixtures thereof. According to U.S. Pat. No. 4,619, 655 tests show that when alloplasts composed of 50/50 mixtures of hydroxylapatite/Plaster of Paris were implanted into experimentally created defects in rat mandible, the Plaster of Paris was completely resorbed within a few weeks and replaced by connective tissue. The hydroxylapatite was not resorbed and some particles were eventually completely surrounded by bone. It was therefore concluded that the Plaster of Paris acted as a scaffold for the incorporation of hydroxylapatite into bone.
A recent study presented on the “Combined Orthopaedic Research Societies Meetings”, Sep. 28-30, 1998, Hamamatsu, Japan, also shows additional tests relating to mixtures of Plaster of Paris and hydroxylapatite. According to this study a combination of hydroxylapatite particles and Plaster of Paris had a viscosity which allowed an easy placement of the implant material and prevented migration of hydroxylapatite particles into surrounding tissues during and after implantation. The experiments showed that Plaster of Paris was absorbed in relatively short time, was easily manipulated with hydroxylapatite particles, and did not interfere with the process of bone healing.
WO 9100252 shows a composition which is capable of hardening in blood within about 10-45 min. The composition comprises essentially calcium sulphate hemihydrate with small amounts of calcium sulphate dihydrate. Organic and inorganic materials, such as hydroxylapatite, can also be included in the composition. After hardening, particles of hydroxylapatite are obtained within a calcium sulphate cement. The calcium sulphate cement is dissolved rapidly by aqueous body fluids within four weeks, leaving solid particles of hydroxylapatite.
Likewise, such particles of hydroxylapatite within a calcium sulphate cement are obtained by the method of WO 9117722. The composition for use as an animal implant comprises calcium sulphate hemihydrate, calcium phosphate, and sodium sulphate. The calcium phosphate is hydroxylapatite and the sodium sulphate enables the composition to be used in the presence of blood or other body fluids.